Synthesis of 4-Substituted 1,5-Dihydropyrrol-2-ones and 5,6-Dihydro-1H-pyridin-2-ones by Negishi Cross-Coupling Reactions: Short Access to the Antidepressant (±)-Rolipram

Abstract

A straightforward access to the title compounds was ­established by Pd-catalyzed Negishi cross-coupling reactions of the readily available bromides 3 and 6 with various functionalized zinc reagents (71-97% yield).

Key words

catalysis - cross-coupling - heterocycles - lactams - palladium - zinc

References and Notes

• Reviews on 1,5-dihydropyrrol-2-ones and 5,6-dihydro-1H-pyridin-2-ones:
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• Individual methods (see also ref. 4) for 4-substituted 1,5-dihydropyrrol-2-ones, see:
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• A 4-stannylated N-Boc-protected 1,5-dihydropyrrol-2-one has been used as nucleophile in Stille cross-coupling reactions:
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7

Typical Procedure for the Bromide Formation with Oxalyl Bromide To a solution of DMF (6.4 mL, 82.3 mmol) in dry CH₂Cl₂ (100 mL) oxalyl bromide (6.8 mL, 73.4 mmol) was added slowly at 0 °C. The reaction mixture was stirred at this temperature until gas formation ceased. Then, 1-tert-butyl-piperidine-2,4-dione (8, 5.24 g, 31.0 mmol) dissolved in dry CH₂Cl₂ (50 mL) was added to the solution at 0 °C. The reaction mixture was stirred for 1 h at 0 °C and for 1 h at r.t. After neutralization with sat. aq NaHCO₃ solution, H₂O (20 mL) and CH₂Cl₂ (20 mL) were added. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL). The organic layers were combined, washed with sat. aq NaCl solution (20 mL) and dried over MgSO₄. After filtration the solvent was evaporated under reduced pressure. After purification by flash chromatography (pentane-EtOAc, 9:1) 4-bromo-1-tert-butyl-5,6-dihydro-1H-pyridin-2-one (4, 5.98 g, 25.9 mmol, 84%) was obtained as colorless liquid. R _f = 0.25 (cyclohexane-EtOAc, 9:1). IR (film): ν_max = 2974, 2868, 1652, 1625, 1461, 1411, 1364, 1352, 1319, 1258, 1242 cm^-1. ¹H NMR (360 MHz, CDCl₃): δ = 1.40 (s, 9 H), 2.68 (dt, ³ J = 6.8 Hz, ⁴ J = 1.4 Hz, 2 H), 3.44 (t, ³ J = 6.8 Hz, 2 H), 6.17 (t, ⁴ J = 1.4 Hz, 1 H) ppm. ¹³C NMR (90.6 MHz, CDCl₃): δ = 28.6 (q), 35.6 (t), 42.2 (t), 57.0 (s), 129.5 (d), 135.7 (q), 164.3 (s) ppm. HMRS (EI): m/z calcd for C₈H₁₁BrNO [M - CH₃]⁺: 216.0024; found: 216.0019. Anal. Calcd for C₉H₁₄BrNO: C, 46.57; H, 6.08; N, 6.03. Found: C, 46.53; H, 6.07; N, 6.12.

11

Representative Cross-Coupling Procedure To a solution of Pd₂(dba)₃ (20 mg, 22.7 µmol) and RuPhos (40 mg, 90.8 µmol) in dry dimethylacetamide (2 mL) 4-bromo-1-tert-butyl-5,6-dihydro-1H-pyridin-2-one (4, 105 mg, 0.454 mmol) was added at r.t. After stirring for 10 min a solution of the organozinc reagent (0.903 mmol) prepared according to procedure A was added at once. After the reaction mixture was stirred at r.t. for 14 h the solvent was removed under reduced pressure. Purification by flash chromatography (pentane-EtOAc, 19:1) yielded 4-butyl-1-tert-butyl-5,6-dihydro-1H-pyridin-2-one (9a, 92.0 mg, 0.441 mmol, 97%) as a colorless liquid. R _f = 0.18 (cyclohexane-EtOAc, 9:1). ¹H NMR (360 MHz, CDCl₃): δ = 0.85 (t, ³ J = 7.2 Hz, 3 H), 1.44-1.21 (m, 13 H), 2.07 (t, ³ J = 7.5 Hz, 2 H), 2.13 (t, ³ J = 6.6 Hz, 2 H), 3.31 (t, ³ J = 6.6 Hz, 2 H), 5.55 (s, 1 H) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 13.8 (q), 22.3 (t), 28.7 (q), 28.8 (t), 29.2 (t), 35.5 (t), 41.8 (t), 56.3 (s), 122.4 (d), 153.3 (s), 167.1 (s) ppm. HMRS (EI): m/z calcd for C₁₃H₂₃NO: 209.1780; found: 209.1782. Anal. Calcd for C₁₃H₂₃NO: C, 74.59; H, 11.07; N, 6.69. Found: C, 74.22; H, 11.30; N, 6.55.

22

Representative Deprotection Procedure 4-(3-Cyclopentyloxy-4-methoxy-phenyl)-2-oxo-2,5-dihydro-pyrrole-1carboxylic acid tert-butyl ester (11i, 36 mg, 96.4 µmol) was dissolved in CH₂Cl₂ (2 mL) at r.t. and TFA (37 µl, 482 µmol) was added. After the reaction mixture was stirred at r.t. for 30 min the solvent and TFA were removed under reduced pressure. Purification by flash chromatography (EtOAc-MeOH, 9:1) yielded 4-(3-cyclopentyloxy-4-methoxy-phenyl)-1,5-dihydro-pyrrol-2-one (25.0 mg, 91.5 µmol, 95%) as colorless crystals. R _f = 0.55 (EtOAc-MeOH, 9:1); mp 203-205 °C. ¹H NMR (360 MHz, CDCl₃): δ = 1.60-1.63 (m, 2 H), 1.81-1.95 (m, 6 H), 3.87 (s, 3 H), 4.37 (s, 2 H), 4.76-4.80 (m, 1 H), 6.29 (s, 1 H), 6.85 (d, ³ J = 8.4 Hz, 1 H), 7.01-7.04 (m, 2 H), 7.14 (s, br, 1 H) ppm. ¹³C NMR (90.6 MHz, CDCl₃): δ = 24.2 (t), 32.9 (t), 48.5 (t), 56.2 (q), 81.0 (d), 111.9 (d), 112.8 (d), 118.2 (d), 119.2 (d), 124.9 (s), 148.1 (s), 152.3 (s), 157.9 (s), 175.8 (s) ppm. HMRS (EI): m/z calcd for C₁₆H₁₉NO₃: 273.1365; found: 273.1361.